This application is a resubmission in response to PA-11-261, entitled Exploratory Developmental Research Grant Program. Methamphetamine (METH) dependence has profound adverse medical, social and societal consequences. A paucity of studies has examined potential medications for treating this disorder, including the efficacy of medications to alleviate METH withdrawal symptoms. Medications development has also been hampered by generally employing study designs that examine the initiation of abstinence, rather preventing relapse. Early abstinence is often associated with withdrawal symptoms and relapse to METH use. A promising therapeutic approach involves the use of indirect agonist pharmacotherapy for METH dependence; however, studies are few and have considerable variability in methodology. Despite successful agonist treatments for dependence on other drugs, including the stimulant nicotine, there has been a reluctance to examine more closely agonist treatment for stimulant dependence for several reasons, including the potential for abuse, psychosis and neurotoxic effects associated with prolonged exposure to amphetamines. Thus, given the potential for alleviating withdrawal utilizing a short term agonist therapy, this proposal will examine the efficacy of the agonist Lisdexamfetamine (LDX) in 1) delaying time to relapse and 2) alleviating withdrawal symptoms in recently abstinent METH-dependent individuals. This 9-wk, randomized, double blind, placebo-controlled clinical trial will provide treatment for 40 METH-dependent (18-65 yrs.) individuals over a two-year period. Participants first will reside at a residential facility (Recovery Centers of Arkansas) to initiate initial drug abstinence and be inducted on the study medication. They will be randomized by sex, severity of dependence and childhood diagnosis of ADHD to receive either placebo (N=20) or LDX (100 mg/day; N=20). Then participants transfer to the Outpatient Treatment Research Program and continue to receive study medication for weeks 2-4 and be tapered off study medication during weeks 5-6. During the outpatient portion of the trial, subjects participate in weekly individual cognitive behavioral therapy. During the trial, participants are given monetary incentives for complying with study requirements. At the end of 9 weeks, patients will have end of study assessments and be referred to an appropriate treatment program. Final assessments to determine longer term efficacy will be obtained at week 13, 4 weeks after study completion. Efficacy will be determined by length of time in treatment, alleviation of withdrawal symptoms, changes in cognitive function, and length of time to lapse/relapse as determined by urine toxicology. The findings of this trial, if positive, will support an R01 application to examine the efficacy of LDX and prognostic relevance of various factors in a larger sample. As such, these findings may shift clinical practice with the development of an efficacious pharmacotherapy for METH dependence.